A key event in an immune response involves the migration of leukocytes to a disease site. During an inflammatory response, leukocytes are recruited to the site of injury and are extravasated by a series of cellular interactions involving cell-cell and cell-substrate adhesion. The administration of compounds that inhibit these cellular interactions of leukocytes provides a route for treating inflammatory or immune diseases.
One family of molecules that serves an important adhesive function is integrins. Integrins are expressed on cell surfaces and function in cell-cell and cell-substrate adhesion. Integrins are alpha-beta heterodimers: each integrin has an alpha (α) subunit non-covalently bound to a beta (β) subunit. There are four known integrins having a β2 or CD18 subunit, which comprise the CD11/CD18 integrin sub-family, namely, Lymphocyte Function-associated Antigen 1 (LFA-1) (CD11a/CD18 or αLβ2); Macrophage Antigen 1 (Mac-1) (CD11b/CD18 or αMβ2); p150,95 (CD11c/CD18 or αXβ2); and αDβ2. The CD11/CD18 family of integrins is also referred to as Leukointegrins as they are expressed on the surface of various leukocyte cells, and they mediate a number of inflammation-related cellular interactions. See Diamond et al., “The Dynamic Regulation of Integrin Adhesiveness,” Current Biology, Vol. 4 (1994) at pp. 506–532.
When activated, the integrins bind to extracellular ligands and induce adhesion. Ligands to LFA-1 and Mac-1 comprise the intercellular adhesion molecule (ICAM) ICAM-1. The primary CD11/CD18 integrin is LFA-1, which also binds with ICAM-2 and ICAM-3. The interaction between the CD18 integrins, particularly LFA-1, and ICAMs mediates antigen presentation, T-cell proliferation, and adhesion between the endothelium and activated leukocytes, which is necessary for leukocytes to migrate from the circulatory system into tissue. Compounds inhibiting CD18 integrins, ICAMs, and/or the LFA-1:ICAM interaction have demonstrated a wide range of utilities in treating inflammatory or immune diseases. Compounds that reportedly inhibit LFA-1/ICAM for use as anti-inflammatory agents include thiadiazole-based compounds (see Intern. Pub. No. WO 99/20,618, “Thiadiazole Amides Useful as Anti-Inflammatory Agents” filed by Pharmacia & Upjohn Co.; and WO 99/20,617, also to Pharmacia and Upjohn); and thiazole compounds linked to phenyl and pyrazole rings (Sanfilippo et al., “Novel Thiazole Based Heterocycles as Inhibitors of LFA-1/ICAM-1 Mediated Cell Adhesion,” J. Med. Chem., Vol. 38 (1995) at pp.1057–1059). Small molecules that reportedly are antagonists to the binding of ICAMs with CD18 integrins include various benzylamines and 2-bromobenzoyltryptophan compounds (see Intern. Pub. No. WO99/49,856, “Antagonists for Treatment of CD11/CD18 Adhesion Receptor Mediated Disorders,” filed by Genentech, Inc.), and 1-(3,5 dichlorophenyl)imidazolidines (see Intern. Pub. No. WO98/39303, “Small Molecules Useful in the Treatment of Inflammatory Disease,” filed by Boehringer Ingelheim Pharmaceuticals, Inc. See also Boehringer patent applications WO 01/07052, WO 01/07048, WO 01/07044, WO 01/06984, and WO 01/07440). Hydantoin compounds are disclosed in Intern. Pub. No's WO 00/59880, WO 00/39081, WO 02/02522, and WO 02/02539 (all to Abbott Laboratories). LFA-1 antagonist compounds are also claimed in WO 02/059114 (to Genentech), WO 02/42294 (to Celltech), WO 01/51508 (to Science and Technology Corporation), WO 00/21920 and WO 01/58853 (both to Hoffmann-LaRoche), WO 99/11258, WO 00/48989 and WO 02/28832 (all to Novartis). Hydantoin compounds are disclosed in Intern. Pub. No. WO 01/30781 A2 (published May 3, 2001) to Tanabe Seiyaku Co. Ltd, “Inhibitors of αLβ2 Mediated Cell Adhesion,” and in Intern. Pub. No. WO 02/44181 (published Jun. 6, 2002), “Hydantoin Compounds Useful as Anti-Inflammatory Agents”, to the present assignee.
Accordingly, compounds that inhibit CD18 integrins, ICAMs, and/or the LFA-1:ICAM interaction could demonstrate a wide range of utilities in treating inflammatory or immune diseases. U.S. Patent Application Publication 2004/0009998 A1 (incorporated herein by reference and assigned to present applicant) discloses aryl or heteroaryl substituted spiro-hydantoin compounds that are antagonists of Leukointegrins and/or ICAMs, for example these compounds inhibit the LFA-1:ICAM interaction. The reference also discloses various processes to prepare these spiro-hydantoins, such as a multistep synthesis that includes the introduction and subsequent removal of protecting groups.
It is desirable to find new compounds with improved pharmacological characteristics compared with known inhibitors of CD18 integrins, ICAMS, and/or the LFA-1:ICAM interaction. For example, it is preferred to find new compounds that demonstrate improved inhibition of the LFA-1:ICAM interaction. It is also desirable and preferable to find compounds with advantageous and improved pharmacological characteristics. Such characteristic include, but are not limited to: (a) pharmaceutical properties; (b) dosage requirements; (c) factors which decrease blood concentration peak-to-trough characteristics; (d) factors, such as increased metabolic stability, that increase the concentration of active drug at the receptor; (e) factors that decrease the liability for clinical drug-drug interactions; (f) factors that decrease the potential for adverse side-effects; and/or (g) factors that improve manufacturing costs or feasibility.
It is also desirable in the art to provide new and/or improved processes to prepare substituted spiro-hydantoin compounds. Such processes may be characterized, without limitation, by a) facile adaptation to larger scale production, such as pilot plant or manufacturing scales; b) process steps and/or techniques enabling improvements in the purity of intermediates and/or final compounds; and/or c) fewer process steps.